CN101330919B - Pharmaceutical composition including (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrim idin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-enoic acid - Google Patents
Pharmaceutical composition including (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrim idin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-enoic acid Download PDFInfo
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Abstract
A chemically stable formulation of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrim idin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically-acceptable salt thereof for oral use, such as tablets, capsules, powders, granules has been developed using the substances which stabilize against formation of degradation products: lactone and oxidation product.
Description
Technical field
The present invention relates to contain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3; 5-dihydroxy heptyl-6-olefin(e) acid or its pharmaceutically acceptable salt (being referred to as " therapeutic agent " hereinafter), the especially pharmaceutical composition of half calcium salt belong to field of pharmaceutical preparations.
Background technology
Said therapeutic agent is patent EP 521471 disclosed a kind of 3-hydroxy-3-methyl glutaryl (HMG) coenzyme A (CoA) reductase inhibitors; Be mixed with pharmaceutical composition (processing medicine), it can be used in treatment hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.Relevant with bulk agent or to be mixed with the subject matter that compositions exists be that therapeutic agent is degraded especially easily.The main degradation products (from patent US 6548513, knowing) that forms is lactone (N-{4-(4-fluorophenyl)-5-[2-(4-hydroxyl-6-oxo-Pentamethylene oxide .-2-yl)-vinyl]-6-isopropyl-pyrimidine-2-base }-N-methyl-Methanesulfomide) and oxidation product (7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-3-hydroxyl-5-oxo-heptan-6-olefin(e) acid).And when being exposed to illumination following time, therapeutic agent is degraded into two diastereoisomeric cyclic products, and is of patent US 2005/0187234A1.Sufficiently stable pharmaceutical preparation is a challenge under the conventional storage requirement for being prepared in the therapeutic agent degraded of being mentioned under moist, acidity, oxygen and illumination condition.
Therapeutic agent or chemical analogue compounds (chemical compound that especially belongs to the HMG-CoA reductase inhibitor) stable can and add inorganic salt (particularly calcium phosphate) realization of Stabilization through pH value in the control preparation (component that adds carbonate for example or bicarbonate) in compositions.Also can use for example butylated hydroxytoluene prevention therapeutic agent oxidation of antioxidant.But the optional use amino sugar comes stabilizing pharmaceutical composition in addition.The pharmaceutical composition of current therapeutic agent with Crestor title listing comprises: 5mg, 10mg, 20mg or 40mg therapeutic agent; Calcium phosphate as the inorganic salt that plays Stabilization; And following non-active ingredient: microcrystalline Cellulose, lactose monohydrate, crospolyvinylpyrrolidone, magnesium stearate, hypromellose, glycerol triacetate, titanium dioxide, yellow ferric oxide and red ferric oxide.
Description of drawings
Accompanying drawing is represented: the main degradation products (lactone form of therapeutic agent; Measure with HPLC) the comparison of amount; Said catabolite is (to be undertaken by ICH guide defined terms: 40 ℃ carrying out accelerated stability test; Relative humidity 75% is stored in the primary package (primary package)) corresponding to forming in the compositions of current commercial preparation and the compositions of the present invention.The Y axle is represented catabolite (lactone) percentage composition (%) that forms, and the X axle representes with the moon to be the time of unit.
Summary of the invention
On the one hand; The invention provides a kind of pharmaceutical composition; This pharmaceutical composition comprises (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid or its pharmaceutically acceptable salt is characterized in that this pharmaceutical composition contains through what HPLC measured and are less than 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-3-hydroxyl of 0.05%-5-oxo-heptan-6-olefin(e) acid.
On the other hand; The present invention is a kind of pharmaceutical composition that comprises therapeutic agent, it is characterized in that this pharmaceutical composition contains through what HPLC measured to be less than N-{4-(4-fluorophenyl)-5-[2-(4-hydroxyl-6-oxo-Pentamethylene oxide .-2-yl)-vinyl]-6-isopropyl-pyrimidine-2-base of 0.5% }-N-methyl-Methanesulfomide and be less than 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-3-hydroxyl of 0.05%-5-oxo-heptan-6-olefin(e) acid through HPLC mensuration.
In a specific embodiments, the present invention is a kind of pharmaceutical composition that comprises therapeutic agent, it is characterized in that at least a composition is selected from first group of material: corn starch, silicified microcrystalline cellulose, cross-linking sodium carboxymethyl cellulose and hypromellose; And/or be selected from second group of material: corn starch, mannitol, hydroxypropyl cellulose and hypromellose.
Therefore, specifically, in one embodiment, it is 10 that pharmaceutical composition will comprise weight ratio: the silicified microcrystalline cellulose of 3-4: 1-2, therapeutic agent, corn starch.More specifically, it also will comprise at least a lubricant of as many as 5%, and said lubricant can be selected from Pulvis Talci and Compritol 888 ATO.Again more specifically; Pharmaceutical composition will comprise therapeutic agent, silicified microcrystalline cellulose, corn starch, lactose, Pulvis Talci, silica sol, Compritol 888 ATO and sodium stearyl fumarate, and their weight ratio is 10: 20-30: 10-17: 50-60: 1-3: 0-0.6: 0-2: 0-1.
Said compositions can be wrapped film-coat, and wherein said coating comprises hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), Polyethylene Glycol and Pulvis Talci.
On the other hand; The invention describes the method that preparation comprises the pharmaceutical composition of therapeutic agent; Said method comprises the following steps: a) with therapeutic agent and mixed with excipients and sieves that to obtain homogeneous mixture, said excipient comprises silicified microcrystalline cellulose and corn starch; B) (choose wantonly) mixture of powders is granulated; C) make mixture of powders (or granule) and mix lubricant; D) mixture of powders (or granule) is pressed into tablet; And e) (chooses wantonly) the tablet coating for preparing in the preceding step; One concrete aspect, wherein, therapeutic agent: silicified microcrystalline cellulose: the weight ratio of corn starch is 10: 10-40: 2-20.
In addition; The present invention is that preparation comprises (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3; The method of the pharmaceutical composition of half calcium salt of 5-dihydroxy heptyl-6-olefin(e) acid is characterized in that said method comprising the steps of: a) with said half calcium salt and excipient mixture dry mixed, wherein excipient mixture comprises lactose, silicified microcrystalline cellulose and corn starch; B) (choose wantonly) and mix other excipient therein; C) hybrid lubricant therein, said lubricant is selected from sodium stearyl fumarate or Compritol 888 ATO, especially Compritol 888 ATO; D) mixture of powders that obtains is pressed into tablet; E) (choose wantonly) the tablet coating for preparing in the preceding step, specifically, said material is respectively with respect to the amount of composition weight: said half calcium salt: 5-20 weight %; Lactose: 40-60 weight %; Silicified microcrystalline cellulose: 20-30 weight %; And corn starch: 1-25 weight %, and (choosing wantonly) bag film-coat.
The invention provides aforementioned pharmaceutical compositions and be used to treat hypercholesterolemia, hyperlipoproteinemia and atherosclerotic purposes, therapeutic agent and silicified microcrystalline cellulose and the corn starch purposes in preparation treatment hypercholesterolemia, hyperlipoproteinemia and atherosclerotic medicine also is provided.
On the other hand; The present invention is that silicified microcrystalline cellulose and corn starch are used for stable (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R that comprises; 5S)-3; The application of the pharmaceutical composition of 5-dihydroxy heptyl-6-olefin(e) acid half calcium salt, specifically, wherein said silicified microcrystalline cellulose and corn starch account for the 10-70% of pharmaceutical composition weight jointly.
The invention provides the new pharmaceutical compositions that comprises following advantage: the formation of long-term (promptly during the shelf life of drug products) the suppression therapy agent catabolite of said composition; Preparation itself is not alkalescence (pH by the aqueous dispersion of preparation confirms that this pH is 6.2), does not add any alkalizing agent yet and stops the therapeutic agent degraded; The art recognized method that pharmaceutical composition makes preparation have the preparation of suitable biopharmaceutics character can realize.
Thereby, lack alkaline components, will damage on the one hand the systemic probability of therapeutic agent body because of the variation of gastrointestinal tract pH and reduce to minimumly, so on the other hand compositions is of value to the patient, because alkaline compositions has side effect to gastric mucosa.According to the aqueous solution of the inventor's inventive compositions or the pH of aqueous dispersion is neutral basically, preferred pH 6-8, and this is to be scattered in the 40ml water and to adopt glass electrode pH meter to record through the tablet that a slice is contained the 40mg therapeutic agent.Can adopt the technical method production compositions of having set up; Preferred direct compression or wet granulation be tabletting then; And the bag film-coat is to prepare final dosage form (for example tablet), and the biopharmaceutics character that simultaneous verification is suitable is for example with comparable dissolution of Crestor and/or bioequivalence.
The present invention is combined in the composition of therapeutic agent and stable therapeutic agent in the pharmaceutical composition.According to two kinds of stability property selection components.In first group be come to light can suppression therapy agent oxidation composition: corn starch, silicified microcrystalline cellulose, cross-linking sodium carboxymethyl cellulose and hypromellose.In second group be come to light can the suppression therapy agent the composition that forms of lactone form: corn starch, mannitol, hydroxypropyl cellulose and hypromellose.In addition, use pharmaceutically acceptable pigment or coloring agent, for example in tablet coating, can also stop therapeutic agent to receive illumination effect to form catabolite.
Preferred selection component and be protected from illumination from two groups, obtaining wherein like this, therapeutic agent is stable pharmaceutical composition.In this type preparation, for oxidation, form lactone and form for the catabolite, therapeutic agent is preferably in several years, more preferably keep stable in time several months.
In one embodiment; The present invention includes a kind of pharmaceutical composition, this pharmaceutical composition comprises therapeutic agent, one or more are selected from first group composition (oxidation inhibition composition), one or more compositions that are selected from second group (lactonize and suppress composition) and one or more filleies (being also referred to as diluent), binding agent, disintegrating agent or lubricant.In addition, can add conventional excipient: for example antiseptic, silicon dioxide flux-regulating agent, antitack agent and stabilizing agent.Should be appreciated that particular excipient can play different effects in pharmaceutical composition, for example can make filler, binding agent and disintegrating agent.
Usually, therapeutic agent will exist with the amount of 1-50%, preferred 3-30% by weight.Usually, be selected from that above-mentioned first group and second group combined amount that plays the material of Stabilization will be up to 90%, preferred 10-70%.The above-mentioned material that plays Stabilization also can have filler (diluent), binding agent or disintegrating agent.Usually, by weight, the amount of one or more other filleies can be up to 90%, preferred 30-70%.Other suitable filler comprises, for example lactose, cellulose and its derivant (for example microcrystalline Cellulose, Powderd cellulose), modified starch, polyalcohols, inorganic salt or normally used in the art other filler.Usually, by weight, the amount of one or more binding agents can be up to 90%, preferred 20-70%.Suitable adhesive comprises, for example polyvinylpyrrolidone, arabic gum, tragakanta, guar gum, pectin, microcrystalline Cellulose, methylcellulose, carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, gelatin and sodium alginate.Suitable disintegrating agent comprises, for example cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, primojel, hydroxypropyl emthylcellulose and hydroxypropyl cellulose.Suitable lubricant comprises, for example magnesium stearate, stearic acid, Palmic acid, calcium stearate, Pulvis Talci, Brazil wax, hydrogenated vegetable oil, mineral oil, Compritol 888 ATO, Polyethylene Glycol and sodium stearyl fumarate.
In a preferred embodiment; Compositions will contain the therapeutic agent of 4-11%; The material that plays Stabilization of 10-50%, preferred total amount about 40%, the material of said Stabilization is selected from the first group of material that comprises corn starch, silicified microcrystalline cellulose, cross-linking sodium carboxymethyl cellulose and hypromellose; With the second group of material that comprises corn starch, mannitol, hydroxypropyl cellulose and hypromellose.The material that plays Stabilization is preferably silicified microcrystalline cellulose, corn starch and primojel, and their weight ratio is preferably 10: 1-2: 0-2.In addition, said composition also comprises 20-80%, preferably approximately the lactose filler of 40-60%; With the lubricant that is up to 5%, preferably talc powder, Compritol 888 ATO and sodium stearyl fumarate.
In a preferred embodiment, the weight ratio of therapeutic agent and silicified microcrystalline cellulose, corn starch, lactose, Pulvis Talci, silica sol, Compritol 888 ATO and sodium stearyl fumarate is 10: 10-40: 2-20: 30-70: 1-10: 0-0.6: 0-3: 0-2.Aforementioned proportion most preferably is 10: 20-30: 10-17: 50-60: 1-3: 0-0.6: 0-2: 0-1.
Standard technique and production method that pharmaceutical composition of the present invention can be used well-known in this area prepare, for example through each composition of dry mixed.Can make each composition or the mixture self of the mixture before mixing pass through screen cloth.Can also in mixture, add lubricant easily, and continue to mix until obtaining homogeneous mixture.Then, mixture is pressed into tablet.Perhaps, can use wet granulation technique.
Through with therapeutic agent and whole excipient (non-active ingredient) dry mixed in double-cone mixer except that lubricant; Preparation comprises (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid half calcium salt and the pharmaceutical composition that is selected from aforementioned first group, second group composition.With lubricant, being Compritol 888 ATO in the embodiment then, is sodium stearyl fumarate in another embodiment, add in the mixture, and the short time (for example making the even needed time of mixture basically, for example as many as 5 minutes) mixes.Then mixture is pressed into tablet, and with comprising film forming polymer (for example hypromellose or hydroxypropyl cellulose), film softening agent (for example Polyethylene Glycol), pigment, talcous conventional coated composition bag film-coat.
According to the inventor's invention, typical compositions comprises (weight):
| Therapeutic agent (half calcium salt) | ?5-20％ |
| Lactose | ?40-60％ |
| Silicified microcrystalline cellulose | ?20-30％ |
| Corn starch | ?1-25％ |
Also contain:
| Fluidizer (Pulvis Talci and/or silica sol) | 0.5-5％ |
| Lubricant (sodium stearyl fumarate and/or Compritol 888 ATO) | 0.1-3％ |
And also optional:
| Primojel | ?0-5％ |
Can carry out tablet coating then, for example through using film coating prescription to carry out spray coating based on water-ethanol.The combination of coating composition is easy to obtain.In embodiments of the invention, the coating that contains pigment or coloring agent reduces the formation speed of the photolytic product of therapeutic agent.
Experimental section
Bulk agent is placed under stress (stress) condition solution of the temperature that for example raises (40 ℃ be higher than 40 ℃), the humidity (relative humidity is 75% or higher, uncovered plate condition), oxygen atmosphere or the different pH that raise.Then, application can be analyzed the HPLC that therapeutic agent and its catabolite separate, and confirms to place the amount (mass percent with respect to therapeutic agent provides) of the catabolite of the sample under the stress condition.Acetonitrile and oxolane gradient eluting on the C18 reversed phase chromatographic column with acid phosphatase salt buffer and increase can obtain good chromatographic isolation.Under the 242nm wavelength, detect, catabolite is carried out quantitatively with UV.The report limit of catabolite is set at 0.05%.The percent of HPLC analysis report is generally area percent.
As raw material (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3; 5-dihydroxy heptyl-6-olefin(e) acid half calcium salt places stress condition following time, and chemical compound generation chemical degradation demonstrates its unstability shown in following result:
| Stress condition | The amount of lactone (%) | The amount of oxidation product (%) |
| The therapeutic agent aqueous solution is buffered to pH=5, at room temperature (24 hours) | 2.30 | ＜0.05 |
| Therapeutic agent is under oxygen atmosphere, 60 ℃ of placements 14 days | 0.17 | 0.71 |
Therapeutic agent is exposed to the result who obtains under the identical stress condition with the mixture of commonly used excipient (for example lactose, cross-linking sodium carboxymethyl cellulose or crospolyvinylpyrrolidone), basically with place stress condition under the result that obtains of bulk agent similar.
Yet, make therapeutic agent and aforesaid first group and second form the mixture be grouped into and be exposed under the stress condition, the amount of the lactone of generation significantly be lower than the amount of the lactone that independent application of treatment agent generates, demonstrate their stability.
With the binary mixture (weight, 1: 1) of any composition of therapeutic agent and first group, under oxygen atmosphere, 60 ℃ of conditions, stored 14 days, there is not oxidation product to generate, the bulk agent that exposes then generates 0.71% oxidation product.
Introducing the work embodiment of two stabilization formulations, is two reference implementation examples (first use tablet excipient commonly used, and second comprises a kind of alkalization excipient) subsequently.
Work embodiment 1
Following pharmaceutical composition is to adopt that said method makes, as to have adopted the composition that is selected from two groups of compositions that play Stabilization new compositions.
| Composition | Function | Weight % |
| Therapeutic agent (calcium salt) | Active component | 9.2 |
| Lactose | Filler | 55.9 |
| Silicified microcrystalline cellulose | Filler, binding agent, disintegrating agent, active component stabilizing agent | 24.4 |
| Corn starch | Filler, binding agent, disintegrating agent, active component stabilizing agent | 3.6 |
| Primojel | Disintegrating agent, active component stabilizing agent | 2.4 |
| Pulvis Talci | Fluidizer | 2.7 |
| Compritol 888 ATO | Lubricant | 1.8 |
The pH of said preparation is 6.2.After (uncovered plate) under the condition of 40 ℃ of temperature, relative humidity 75% placed 14 days, the amount of lactone was merely 0.50%.Do not generate oxidation product.
40 ℃, in antiseepage packing after 6 months, the amount of lactone surpasses 0.25%.40 ℃, in antiseepage packing after 6 months, the amount of oxidation product is merely 0.05% or lower.By contrast, the lactone in the for example current commercially available pharmaceutical composition (accompanying drawing) of the pharmaceutical composition of therapeutic agent and the amount of oxidation product are respectively 0.51% and 0.38%.
The tablet film-coat (coating be coated tablet heavy 2.5%) contain hypromellose, hydroxypropyl cellulose, Polyethylene Glycol, pigment and Pulvis Talci, it is to the formation not influence basically of lactone or oxidation product.
Work embodiment 2
| Composition | Function | Weight % |
| Therapeutic agent (calcium salt) | Active component | 9.2 |
| Lactose | Filler | 48.9 |
| Silica sol | Fluidizer | 0.3 |
| Silicified microcrystalline cellulose | Filler, binding agent, disintegrating agent, active component stabilizing agent | 25.0 |
| Corn starch | Filler, binding agent, disintegrating agent, active component stabilizing agent | 15.0 |
| Pulvis Talci | Fluidizer | 1.0 |
| Sodium stearyl fumarate | Lubricant | 0.6 |
To tablet bag film-coat (coating be coated tablet heavy 2.5%), said film-coat contains hypromellose, hydroxypropyl cellulose, Polyethylene Glycol, pigment and Pulvis Talci.
The pH of said preparation is 6.3.Under 40 ℃, relative humidity 75% condition (uncovered plate) after 14 days, the amount of lactone is merely 0.35-0.43%.Do not generate oxidation product.
Reference implementation example 1
Following is the compositions that comprises the conventional excipients that therapeutic agent and lactose manufacturer DMV provide.Same procedure according to above-mentioned work embodiment prepares tablet.The unstability of therapeutic agent in the bright compositions of the scale of catabolite.
| Composition | Function | Weight % |
| Therapeutic agent (calcium salt) | Active component | 9.4 |
| Lactis Anhydrous | Filler, binding agent | 41.7 |
| Silica sol | Fluidizer | 0.3 |
| The lactose that sieved | Filler | 41.7 |
| Croscarmellose sodium | Disintegrating agent | 4.0 |
| Pulvis Talci | Fluidizer | 1.0 |
| Compritol 888 ATO | Lubricant | 1.8 |
Under 40 ℃, the condition of relative humidity 75% (uncovered plate) after 14 days, the amount of lactone is 2.32%.
Reference implementation example 2
Following is to comprise therapeutic agent and like (the pharmaceutical dosage form: tablet (pharmaceutical dosage forms:Tablets) the 1st volume, Herbert, Lieberman, Lachman and Schwartz of textbook in this category; Marcel Dekker, New York and Basel; The compositions of the conventional excipients of second edition in 1989) being said.In said composition, add basifier.Same procedure according among the above-mentioned work embodiment prepares tablet.
Under the condition that basifier exists, the compositions display therapeutic agent is stable.Under 40 ℃, relative humidity 75% condition, in uncovered plate, place after 1 month, the amount of lactone is 0.07%.Think that sample has good stable property because alkaline.
Reference implementation example 3
[0059] the parallel stability of estimating current commercially available prod.After 2 months, the amount of lactone is increased to 0.35% from 0.10% at 40 ℃, the condition held of relative humidity 75%; 60 ℃, be exposed in the oxygen place 10 days after, the amount of lactone is increased to 0.40% from 0.10%.Oxidation product keeps being all 0.3% under first kind of condition, under second kind of condition, increases to 0.4%.
Claims (16)
1. pharmaceutical composition; This pharmaceutical composition comprises silicified microcrystalline cellulose, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3; 5-dihydroxy heptyl-6-olefin(e) acid or its pharmaceutically acceptable salt and corn starch, their weight ratio are 10: 3-4: 1-2.
2. according to the pharmaceutical composition of claim 1, this pharmaceutical composition comprises and is up to 5% at least a lubricant that is selected from Pulvis Talci and Compritol 888 ATO.
3. pharmaceutical composition; This pharmaceutical composition comprises (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3; 5-dihydroxy heptyl-6-olefin(e) acid or its pharmaceutically acceptable salt, silicified microcrystalline cellulose, corn starch, lactose, Pulvis Talci, silica sol, Compritol 888 ATO and sodium stearyl fumarate, their weight ratio are 10: 20-30: 10-17: 50-60: 1-3: 0-0.6: 0-2: 0-1.
4. pharmaceutical composition, this pharmaceutical composition comprise (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid half calcium salt, lactose, silicified microcrystalline cellulose and corn starch.
5. according to the pharmaceutical composition of claim 4, this pharmaceutical composition comprises at least a fluidizer that is selected from Pulvis Talci or silica sol in addition.
6. according to the pharmaceutical composition of claim 4 or 5, this pharmaceutical composition comprises at least a lubricant that is selected from sodium stearyl fumarate or Compritol 888 ATO in addition.
7. according to the pharmaceutical composition of claim 1 or 4, the aqueous solution of wherein said compositions or the pH of dispersion are between 6-8, and this is to be dispersed in the 40ml water and to adopt glass electrode pH meter to record through the tablet that a slice is contained the 40mg therapeutic agent.
8. preparing and comprising weight ratio is 10: the silicified microcrystalline cellulose of 3-4: 1-2, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3; The method of the pharmaceutical composition of 5-dihydroxy heptyl-6-olefin(e) acid or its pharmaceutically acceptable salt and corn starch is characterized in that this method may further comprise the steps:
A) with (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3; 5-dihydroxy heptyl-6-olefin(e) acid or its pharmaceutically acceptable salt and mixed with excipients are also sieved; To obtain homogeneous mixture, said excipient comprises silicified microcrystalline cellulose and corn starch;
B) optional mixture of powders is granulated;
C) make mixture of powders or granule and mix lubricant;
D) mixture of powders or granule are pressed into tablet;
E) optional with the tablet coating for preparing in the preceding step.
The preparation comprise (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R, 5S)-3, the method for the pharmaceutical composition of half calcium salt of 5-dihydroxy heptyl-6-olefin(e) acid is characterized in that this method may further comprise the steps:
A) dry mixed (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3; Half calcium salt and the excipient mixture of 5-dihydroxy heptyl-6-olefin(e) acid, wherein said excipient mixture comprises lactose, silicified microcrystalline cellulose and corn starch;
B) optional other excipient that mixes therein;
C) mix the lubricant that is selected from sodium stearyl fumarate or Compritol 888 ATO therein;
D) mixture of powders that makes is pressed into tablet;
E) optional with the tablet coating for preparing in the preceding step.
10. according to the method for claim 9, final composition weight meter relatively wherein, the amount of calculating by weight of following material is:
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid half calcium salt: 5-20%;
Lactose: 40-60%;
Silicified microcrystalline cellulose: 20-30%; With
Corn starch: 1-25%.
11. silicified microcrystalline cellulose and corn starch be used for stable comprise (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R, 5S)-3, the purposes of the pharmaceutical composition of 5-dihydroxy heptyl-6-olefin(e) acid half calcium salt.
12. according to the purposes of claim 11, wherein said silicified microcrystalline cellulose and corn starch account for the 10-70% of pharmaceutical composition weight jointly.
13. according to the purposes of claim 11 or 12, the aqueous solution of wherein said compositions or the pH of dispersion are between 6-8, this is to be dispersed in the 40ml water and to adopt glass electrode pH meter to record through the tablet that a slice is contained the 40mg therapeutic agent.
14. according to the purposes of pharmaceutical composition any among the claim 1-7 in preparation treatment hypercholesterolemia, hyperlipoproteinemia and atherosclerotic medicine.
15. according to claim 1 and 4 pharmaceutical composition, this pharmaceutical composition contain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid or its pharmaceutically acceptable salt,
It is characterized in that: it is stored in the primary package, under 40 ℃ and 75% relative humidity, carries out 6 months stability experiment, and it contains through what HPLC measured and is less than N-{4-(4-fluorophenyl)-5-[2-(4-hydroxyl-6-oxo-Pentamethylene oxide .-2-yl)-vinyl]-6-isopropyl-pyrimidine-2-base of 0.5% }-N-methyl-Methanesulfomide and be less than 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-3-hydroxyl of 0.05%-5-oxo-heptan-6-olefin(e) acid through HPLC mensuration.
16. pharmaceutical composition according to claim 15; The % that wherein measures through HPLC refers to respect to (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-yl]-(3R; 5S)-3, the percent of the amount of 5-dihydroxy heptyl-6-olefin(e) acid or its pharmaceutically acceptable salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200500344 | 2005-12-20 | ||
| SIP200500344 | 2005-12-20 | ||
| PCT/EP2006/012180 WO2007071357A2 (en) | 2005-12-20 | 2006-12-18 | Pharmaceutical composition comprising (e) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5 -yl- (3r, 5s) -3, 5-dihydr0xyhept-6-en0ic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101330919A CN101330919A (en) | 2008-12-24 |
| CN101330919B true CN101330919B (en) | 2012-12-05 |
Family
ID=37866173
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006800476115A Expired - Fee Related CN101330919B (en) | 2005-12-20 | 2006-12-18 | Pharmaceutical composition including (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrim idin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-enoic acid |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20090093499A1 (en) |
| EP (1) | EP1968593B1 (en) |
| JP (1) | JP5235676B2 (en) |
| CN (1) | CN101330919B (en) |
| AU (1) | AU2006329006B2 (en) |
| BR (1) | BRPI0620629B8 (en) |
| CA (1) | CA2630704C (en) |
| EA (1) | EA015682B1 (en) |
| WO (1) | WO2007071357A2 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20080060284A (en) | 2006-09-18 | 2008-07-01 | 테바 파마슈티컬 인더스트리즈 리미티드 | Crystalline rosuvastatin calcium |
| MX2010008466A (en) * | 2008-01-30 | 2010-10-25 | Lupin Ltd | Modified release formulations of hmg coa reductase inhibitors. |
| EP2138165A1 (en) | 2008-06-27 | 2009-12-30 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition comprising a statin |
| ES2657416T3 (en) * | 2008-06-27 | 2018-03-05 | Krka, Torvarna Zdravil, D.D., Novo Mesto | Pharmaceutical composition comprising a statin |
| PL386051A1 (en) * | 2008-09-09 | 2010-03-15 | Zakłady Farmaceutyczne POLPHARMA Spółka Akcyjna | Stable, oral compound pharmaceutical containing pharmaceutically permissible content of [(E)-7-[4-(4-fluorphenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R,5S)-3,5-dihydroxy-hept-6-enoate acid salt |
| TR200902077A2 (en) | 2009-03-17 | 2010-01-21 | Sanovel İlaç San.Veti̇c.A.Ş. | Stable rosuvastatin compositions |
| RU2606592C1 (en) * | 2015-10-07 | 2017-01-10 | Открытое Акционерное Общество "Татхимфармпрепараты" | Pharmaceutical composition containing rosuvastatin calcium salt (versions) |
| MX2022006873A (en) * | 2019-12-31 | 2022-08-18 | Pfizer R&D Uk Ltd | Stable immediate release tablet and capsule formulations of 1-((2s,5r)-5-((7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylp iperidin-1-yl)prop-2-en-1-one. |
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|---|---|---|---|---|
| JP2648897B2 (en) * | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | Pyrimidine derivatives |
| GB0000710D0 (en) | 1999-02-06 | 2000-03-08 | Zeneca Ltd | Drug combination |
| GB0001621D0 (en) * | 2000-01-26 | 2000-03-15 | Astrazeneca Ab | Pharmaceutical compositions |
| US6399101B1 (en) * | 2000-03-30 | 2002-06-04 | Mova Pharmaceutical Corp. | Stable thyroid hormone preparations and method of making same |
| AU2002244295B2 (en) * | 2001-03-13 | 2006-02-09 | Penwest Pharmaceuticals Co. | Chronotherapeutic dosage forms containing glucocorticosteroid |
| SE0101329D0 (en) * | 2001-04-12 | 2001-04-12 | Astrazeneca Ab | Pharmaceutical formulation |
| GB0111077D0 (en) * | 2001-05-04 | 2001-06-27 | Biochemie Gmbh | Organic compounds |
| US20030215502A1 (en) * | 2002-03-20 | 2003-11-20 | Elan Pharma International Limited | Fast dissolving dosage forms having reduced friability |
| WO2003090723A1 (en) * | 2002-04-23 | 2003-11-06 | Bristol-Myers Squibb Company | Modified-release vasopeptidase inhibitor formulation, combinations and method |
| WO2003092729A1 (en) * | 2002-05-03 | 2003-11-13 | Hexal Ag | Stable pharmaceutical formulation for a combination of a statin and an ace inhibitor |
| SI21402A (en) * | 2003-02-12 | 2004-08-31 | LEK farmacevtska dru�ba d.d. | Lined particles and pharmaceutical forms |
| EP1678148A1 (en) * | 2003-10-22 | 2006-07-12 | Ranbaxy Laboratories Limited | Process for the preparation of amorphous rosuvastatin calcium |
| US8987322B2 (en) * | 2003-11-04 | 2015-03-24 | Circ Pharma Research And Development Limited | Pharmaceutical formulations for carrier-mediated transport statins and uses thereof |
| WO2005077916A1 (en) * | 2004-01-19 | 2005-08-25 | Ranbaxy Laboratories Limited | Salts of hmg-coa reductase inhibitors and use thereof |
| KR100887264B1 (en) * | 2003-12-02 | 2009-03-06 | 테바 파마슈티컬 인더스트리즈 리미티드 | Reference standard for characterization of rosuvastatin |
| WO2005077917A1 (en) * | 2004-01-19 | 2005-08-25 | Ranbaxy Laboratories Limited | Amorphous salts of rosuvastatin |
-
2006
- 2006-12-18 AU AU2006329006A patent/AU2006329006B2/en not_active Ceased
- 2006-12-18 CA CA2630704A patent/CA2630704C/en not_active Expired - Fee Related
- 2006-12-18 CN CN2006800476115A patent/CN101330919B/en not_active Expired - Fee Related
- 2006-12-18 EA EA200801447A patent/EA015682B1/en not_active IP Right Cessation
- 2006-12-18 JP JP2008546216A patent/JP5235676B2/en not_active Expired - Fee Related
- 2006-12-18 WO PCT/EP2006/012180 patent/WO2007071357A2/en active Application Filing
- 2006-12-18 US US12/158,413 patent/US20090093499A1/en not_active Abandoned
- 2006-12-18 EP EP06829701.9A patent/EP1968593B1/en not_active Not-in-force
- 2006-12-18 BR BRPI0620629A patent/BRPI0620629B8/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0620629B1 (en) | 2020-01-14 |
| CA2630704C (en) | 2014-08-19 |
| EP1968593B1 (en) | 2017-08-23 |
| WO2007071357A3 (en) | 2007-11-08 |
| CN101330919A (en) | 2008-12-24 |
| EA200801447A1 (en) | 2008-12-30 |
| BRPI0620629B8 (en) | 2021-05-25 |
| CA2630704A1 (en) | 2007-06-28 |
| WO2007071357A2 (en) | 2007-06-28 |
| JP5235676B2 (en) | 2013-07-10 |
| EP1968593A2 (en) | 2008-09-17 |
| EA015682B1 (en) | 2011-10-31 |
| AU2006329006A1 (en) | 2007-06-28 |
| AU2006329006B2 (en) | 2013-02-28 |
| US20090093499A1 (en) | 2009-04-09 |
| BRPI0620629A2 (en) | 2011-11-16 |
| JP2009519985A (en) | 2009-05-21 |
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